Models of psychedelic drug action: modulation of cortical-subcortical circuits
Manoj K. Doss, Maxwell B. Madden, Andrew Gaddis, Mary Beth Nebel, Roland R. Griffiths, Brian N. Mathur, Frederick S. Barrett
Brain October 22, 2021 DOI: 10.1093/brain/awab406 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Default mode network Psilocybin |
| Keywords | Circuit models Claustrum Thalamus Psychedelics: psychedelic drugs Psychedelic experience Therapeutic promise Brain circuits Brain region Serotonin receptors Cortical networks Psychiatric disorders |
| Citations | 196 |
| Key findings | A third circuit-level model (CCC) involving the claustrum is introduced to explain psychedelic drug effects alongside the CSTC and REBUS models. |
Abstract
Abstract Classic psychedelic drugs such as psilocybin and lysergic acid diethylamide (LSD) have recaptured the imagination of both science and popular culture, and may have efficacy in treating a wide range of psychiatric disorders. Human and animal studies of psychedelic drug action in the brain have demonstrated the involvement of the serotonin 2A (5-HT2A) receptor and the cerebral cortex in acute psychedelic drug action, but different models have evolved to try to explain the impact of 5-HT2A activation on neural systems. Two prominent models of psychedelic drug action (the cortico-striatal thalamo-cortical, or CSTC, model and relaxed beliefs under psychedelics, or REBUS, model) have emphasized the role of different subcortical structures as crucial in mediating psychedelic drug effects. We describe these models and discuss gaps in knowledge, inconsistencies in the literature and extensions of both models. We then introduce a third circuit-level model involving the claustrum, a thin strip of grey matter between the insula and the external capsule that densely expresses 5-HT2A receptors (the cortico-claustro-cortical, or CCC, model). In this model, we propose that the claustrum entrains canonical cortical network states, and that psychedelic drugs disrupt 5-HT2A-mediated network coupling between the claustrum and the cortex, leading to attenuation of canonical cortical networks during psychedelic drug effects. Together, these three models may explain many phenomena of the psychedelic experience, and using this framework, future research may help to delineate the functional specificity of each circuit to the action of both serotonergic and non-serotonergic hallucinogens.
Comparable studies
Other narrative reviews on default mode network, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| The Brain's Default Mode Network | 2015 | Review | |
| Default Mode Network Activity and Connectivity in Psychopathology | 2012 | Review | |
| 20 years of the default mode network: A review and synthesis | 2023 | Review | |
| On the relationship between the “default mode network” and the “social brain” | 2012 | Review | |
| The default mode network and social understanding of others: what do brain connectivity studies tell us Healthy subjects, with some studies on patients with autism and psychopathy | 2014 | Review |
Citations in the library
Cited by 156
- The neural basis of psychedelic action. Nature Neuroscience October 24, 2022
- Default Mode Network Modulation by Psychedelics: A Systematic Review The International Journal of Neuropsychopharmacology October 21, 2022
- Pharmacological, neural, and psychological mechanisms underlying psychedelics: a critical review Neuroscience & Biobehavioral Reviews September 1, 2022
- Receptor-informed network control theory links LSD and psilocybin to a flattening of the brain's control energy landscape. Nature Communications October 3, 2022
- Psychedelics and Neural Plasticity: Therapeutic Implications. Journal of Neuroscience November 1, 2022
and 151 more in the library
Cites 103
- A default mode of brain function Proceedings of the National Academy of Sciences January 16, 2001
- The Brain's Default Mode Network Annual Review of Neuroscience May 4, 2015
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance Psychopharmacology July 7, 2006
and 98 more in the library